Post-Transplant Cyclophosphamide for Gvhd Prophylaxis in Matched Unrelated Donor Transplantation Compared to ATG-Based Prophylaxis

Background: Post-transplant high dose cyclophosphamide (PT-CY) effectively prevents graft-versus-host disease (GVHD) after unmanipulated HLA-haploidentical hematopoietic stem cell transplantation (HSCT). The use of PT-CY in HLA-identical donor is less explored. In this study, we analyzed the results of PT-CY for GVHD prophylaxis in matched unrelated donor (MUD) HSCT and compared them with those obtained after prophylaxis with anti-thymocyte globulin (ATG), methotrexate (MTX) and cyclosporine (CsA). Methods: 132 matched unrelated donor HSCT from 4 Spanish centers have been analyzed: 60 performed between 2010 and 2018 using ATG-MTX-CsA and 72 performed between 2014 and 2018 using PT-CY. Results: Baseline characteristics and post-transplant complications are shown in Table 1. Peripheral blood was used as graft source in 92% of the patients in the ATG group and in 78% in the PT-CY group. GVHD prophylaxis consisted in rabbit ATG either 2mg/kg days -4 to -2 (41 patients, 68%) or 0.5mg/m2 on day -3 followed by 1mg/kg days -2 and -3 (19 patients, 32%), MTX days +1, +3, +6 and +11, and CsA from day -1 in the ATG group. The PT-CY group received cyclophosphamide 50 mg/kg/d on days +3 and +4, followed by either CsA or tacrolimus plus mycophenolate mofetil (MMF) from day +5 in 30 patients (42%), or cyclophosphamide on days +3 and +5 combined with CsA or tacrolimus in 42 patients (58%; 16 out of them also received sirolimus due to 9/10 HLA-match). Cumulative incidence of grade II-IV (67% vs 46%, p=0.008) and III-IV (34% vs 3%, p=0.003) acute GVHD, were significantly higher in the ATG group (Figure 1). There were no differences in the 2-year cumulative incidence of chronic moderate to severe GVHD (23% vs 24%, p=0.86). After a median follow-up of 78 months for the ATG group and 26 months for the PT-CY group, no differences were found in the 2-year overall survival (58% vs 60%, p=0.475), 2-year event-free survival (51% vs 50%, p=0.961) and the composite endpoint of GVHD-free and relapse-free survival (44% vs 40%, p=0.742). The 2-year cumulative incidence of relapse (22% vs 26%, p=0.67) and non-relapse mortality (NRM) (24% vs 22%, p=0.68) were also similar between both groups. However, NRM in the ATG group was due to GVHD in 9 out of 16 patients, while in the PT-CY group NRM was mostly due to infections and organ toxicity and only 3 out of 15 patients died due to GVHD. The incidence of sinusoidal obstruction syndrome was low in both groups (0% vs 4%, p=0.11). CMV reactivation rates were similar (40% vs 51%, p=0.191). However, both hemorrhagic cystitis and EBV reactivation were higher in the ATG group (56% vs 12%, p=0.00, and 5% vs 0%, p=0.05, respectively). Conclusions: In our experience, GVHD prophylaxis using PT-CY combined with additional immunosuppression after MUD HSCT, using mostly peripheral blood as graft source, resulted in lower incidence of aGVHD compared to prophylaxis based on ATG-MTX-CsA. Although no impact on non-relapse mortality was observed, GVHD associated mortality was higher in the ATG group as well as cystitis and EBV reactivations. Prospective studies with longer follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

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Post-Transplant Cyclophosphamide Versus MTX-CSA As Gvhd Prophylaxis in HLA-Identical Sibling HSCT

Blood ◽

10.1182/blood-2018-99-110551 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3394-3394

Author(s):

Rebeca Bailén ◽

Maria-Jesús Pascual ◽

Pascual Balsalobre ◽

Anabel Gallardo-Morillo ◽

Abel García-Sola ◽

...

Keyword(s):

Cumulative Incidence ◽

Acute Gvhd ◽

Conflicts Of Interest ◽

Conditioning Regimen ◽

High Dose ◽

Hematopoietic Stem ◽

Free Survival ◽

Post Transplant ◽

Gvhd Prophylaxis

Abstract Background: Post-transplant high dose cyclophosphamide (PT-CY) effectively prevents graft-versus-host disease (GVHD) after HLA-haploidentical hematopoietic stem cell transplantation (HSCT). However, the use of PT-CY in HLA-identical HSCT is less explored. In this study, we analyzed the results of PT-CY as GVHD prophylaxis in HLA-identical sibling HSCT and compared them with those obtained after prophylaxis with methotrexate (MTX) plus cyclosporine (CsA). Methods: 107 HLA-identical sibling (10/10) HSCT from 2 Spanish centers have been analyzed: 50 performed consecutively between 2010 and 2015 using MTX-CsA as GVHD prophylaxis, and 57 performed consecutively between 2014 and 2018 using PT-CY. Results: Baseline characteristics and post-transplant complications are shown in Table 1. GVHD prophylaxis consisted in MTX days +1, +3, +6 and +11, and CsA from day -1 in the MTX-CsA group. The PT-CY group received cyclophosphamide 50 mg/kg/d on days +3 and +5 in 38 patients (65%), combined with CsA from day +5, and cyclophosphamide on days +3 and +4 in 19 patients (35%), followed by CsA and mycophenolate mofetil from day +5. Graft source was PBSC in 96% in the MTX-CsA group and 86% in the PT-CY group. Conditioning regimen was myeloablative in 64% and 40%, respectively. Neutrophil and platelet engraftment was significantly delayed in the PT-CY group (14.5 (11-27) vs 15.5 (13-37), p=0.02; 11.5 (8-180) vs 20.5 (10-43), p=0.02). After a median follow-up of 60 months for the MTX-CsA group and 15 months for the PT-CY group, 2-year overall survival (OS) was 56% (42-70) and 78% (67-90) (p=0.088), and event-free survival (EFS) was 48% (34-62) and 62.5% (42.5-82.5) (p=0.054), respectively. Cumulative incidence at 100 days of grade II-IV (52.2% vs. 22.6%, p=0.0015), and III-IV (24.4% vs. 8.8%, p=0.016) acute GVHD were significantly higher in the MTX-CsA group (Figure 1A). No differences were observed in the 2-year cumulative incidence of chronic moderate to severe GVHD (26% vs. 16.7% (p=0.306)). No differences were observed in the 2-years cumulative incidence of relapse (27% vs. 28% (p=0.47)). Non-relapse mortality (NRM) at 2-years showed a higher trend in the MTX-CsA cohort (24% vs. 8.8%, p=0.054). Finally, the composite endpoint of GVHD and relapse-free survival (GRFS) at 2-years was significantly better in the PT-CY group (48% vs. 24%, p=0.011) (Figure 1B). Conclusions: In our experience, GVHD prophylaxis using PT-CY combined with additional immunosuppression after HLA-identical sibling HSCT, using mostly peripheral blood as graft source, reduced the cumulative incidence of acute GVHD compared to standard prophylaxis with MTX-CsA, leading to an impact on GRFS. To our knowledge, this is the largest comparative retrospective cohort reported. Further prospective studies with longer follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

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Allogeneic Hematopoietic Stem Cell Transplantation for Myelofibrosis: PK Guided IV Busulfan Dose Intensity Results in Improved Event Free Survival

Blood ◽

10.1182/blood.v118.21.2006.2006 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2006-2006

Author(s):

Uday Popat ◽

Borje S Andersson ◽

Roland Bassett ◽

Stefan Ciurea ◽

Gabriela Rondon ◽

...

Keyword(s):

Stem Cell ◽

Peripheral Blood ◽

Cumulative Incidence ◽

Research Funding ◽

High Dose ◽

Unrelated Donor ◽

Event Free Survival ◽

High Group ◽

Hematopoietic Stem ◽

Free Survival

Abstract Abstract 2006 Background: Allogeneic hematopoietic stem cell transplantation (HCT) is an effective treatment for patients with advanced myelofibrosis. Myeloablative regimens have produced a high rate of morbidity and mortality. Reduced intensity conditioning (RIC) with allogeneic transplantation is being investigated with the goal of reducing non-relapse mortality. There is concern that this benefit might occur at expense of a higher relapse rate. In 2006 we initiated a study of RIC regimen of fludarabine 40mg/m2 (days −5, −4, −3 −2) and IV busulfan 130mg/m2 (day −3,−2). In the first 14 patients (the Bu-low group), 9 patients relapsed. We hypothesized that high dose PK guided IV busulfan would decrease relapse rate without substantially increasing non relapse mortality, thereby improving event free survival (EFS). The next 19 patients received an increased intensity of busulfan (Bu-high group), using pharmacokinetic dose adjustment. Methods: Patients with intermediate or high risk MF were eligible if they had adequate organ function and at least 9/10 matched related or unrelated donor. Patients received IV busulfan dose to a target daily AUC of 4000 μmol/L × 4days (days −5, −4, −3 −2) Fludarabine 40mg/m2 (days −5, −4, −3 −2). Average busulfan dose in Bu-high group was 473 mg/m2 (range 304–886 mg/m2) or 10.8 mg/kg, and it was 260mg/m2 or 6.5mg/kg in Bu-low group. Both cohorts of patients received tacrolimus and mini methotrexate as graft versus host disease prophylaxis and similar supportive care. Thymoglobulin 2.5 mg/kg × 3 (day −3,−2 and 1) was given to all patients receiving an unrelated donor graft. Results: Between 1/2006 and 12/2010, 33 consecutive patients with myelofibrosis were treated including 14 in the Bu-low and 19 in the Bu-high groups. Patients and disease characteristics were similar for the two treatment groups. There were 16 males and 17 females with a median age of 59 (range 27–70). Eighteen patients had primary MF, 8 post PV MF and 7 Post ET MF. Based on Lille criteria, 17 patients had intermediate risk disease and 16 had high risk disease. Eleven patients had splenectomy prior to transplant; remaining 22 patients had enlarged spleen at the time of transplant. Twenty patients had mutated Jak 2. Median peripheral blood CD 34 count was 54/μl (range 1–16426/μl). Karyotype was abnormal in 12 patients and diploid in 21. Donors were matched siblings for 12 patients, matched unrelated for 17, and one antigen or allele mismatched unrelated for 4 patients. Stem cell source was marrow in 4 and peripheral blood in 29. Circulating blasts were present in 17 patients. All patients engrafted with a median time to neutrophil engraftment of 13 days (0–27) days and a median time to platelet engraftment of 18 (0–105) days. Cumulative incidence of acute GVHD was 28% and chronic GVHD 35% (limited 7%, extensive 28%). Cumulative incidence of non relapse mortality was 10% with overall 3 treatment related deaths: 1 in Bu-high group and 2 in Bu-low group (p=0.44). With a median follow up of 1.6 (0.2–5) years, current EFS (p=0.02) and the cumulative incidence of relapse (p=0.04) were significantly different between Bu-high and Bu-low groups, while overall survival (OS) was not (0.28). Two year estimates for the Bu-high and Bu-low groups are as follows: EFS: 69% and 29%; OS: 87% and 71%; cumulative incidence of relapse: 26% and 57%. Multivariate analysis showed that Bu-high dose (HR 0.25; p=0.01) and peripheral blood CD 34 count >100 μl (HR 3.56; p=0.02) were significant predictors of EFS. Conclusion: Higher dose busulfan, delivered with pharmacokinetic dose adjustment, reduces relapse without increasing non relapse mortality, resulting in better EFS in patients with MF. Disclosures: Popat: Otsuka: Research Funding. Andersson:Otsuka American Pharmaceuticals, Inc.: Consultant for Clinical Protocol Development. Nieto:Otsuka: Research Funding. Qazilbash:Otsuka: Research Funding. Champlin:Otsuka: Research Funding.

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De-Escalation of Ptcy Dosing in Matched Allogenic Transplants: A Single Institution Retrospective Study

Blood ◽

10.1182/blood-2021-153455 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4872-4872

Author(s):

Haritha Ackula ◽

Georgio Medawar ◽

Caroline Cerio ◽

Todd F. Roberts ◽

Kapil Meleveedu

Keyword(s):

Phase I ◽

Cell Transplantation ◽

Viral Reactivation ◽

High Dose ◽

Unrelated Donor ◽

Matched Unrelated Donor ◽

Post Transplantation ◽

Post Transplant ◽

Gvhd Prophylaxis

Abstract Introduction The role of post-transplant cyclophosphamide (PTCy) in preventing acute GVHD (aGVHD) and chronic GVHD (cGVHD) has been well established in the haploidentical setting (Al-Homsi AS et al., Post-transplant high-dose cyclophosphamide for the prevention of graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21(4):604-611). More recently, several studies are also supporting its use in matched related and unrelated donors (Williams L et al., Post-transplantation Cyclophosphamide: From HLA-Haploidentical to Matched-Related and Matched-Unrelated Donor Blood and Marrow Transplantation. Front Immunol. 2020;11(April):1-7). But as new emerging data are starting to show some toxicities from that regimen, a reevaluation of the optimal PTCy dose is highly valuable (Duléry R et al., Early Cardiac Toxicity Associated with Post-Transplant Cyclophosphamide in Allogeneic Stem Cell Transplantation. JACC CardioOncology. 2021;3(2):250-259; Goldsmith et al., Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis. Blood. 2021;137(23):3291-3305). PTCy dose de-escalation in preventing GvHD was also evaluated in a phase I/II study (NCT03983850) with initial results indicating that de-escalation of PTCy (DL2, 25 mg/kg/day given in Days 3−4) may provide a feasible and effective approach in preventing severe aGvHD(McAdams MJ et al., Phase I Study De-Intensifying Exposure of Post-Transplantation Cyclophosphamide (PTCy) after HLA-Haploidentical Hematopoietic Cell Transplantation (HCT) for Hematologic Malignancies. Transplant Cell Ther Off Publ Am Soc Transplant Cell Ther. 2021;27(3): S9-S11). However, this was in the setting of haplo-identical transplants. Currently there are no studies that investigate the safety and efficacy of a lower dose of PTCy in matched allogenic transplants. Methods We retrospectively selected 37 consecutive patients who underwent transplant at our center from January 2017 to April 2021. Patients who received a mismatched or haploidentical transplants were excluded. 26 matched sibling or matched unrelated donor transplants were further analyzed. These were divided into 3 cohorts according to GVHD prophylaxis: cohort 1 (No-PTCy) received standard calcineurin inhibitor-methotrexate based GVHD prophylaxis (n=16), cohort 2 (PTCy-50) received PTCy at 50 mg/kg (D+3 and D+4) in combination other immunosuppressive drugs (ISD) (n=6), and cohort 3 (PTCy-25) received PTCy at 25 mg/kg (D+3 and D+4) in combination with other ISD (n=4). The reduced PTCy dosing was based on physician discretion due to various reasons (2 cardiac risk, 1 heavy pre-treatment, 1 unknown). Results Baseline characteristics are summarized in table 1. Median follow up for all survivors was 523 days (range, 97-1463) while it was shorter for PTCy cohorts at 152 days (97-534). There were zero grade 3 aGVHD in PTCy groups compared to 12.5% (2/16) in No-PTCy cohort (p=0.30). cGVHD was significantly lower in PTCy-50 and PTCy-25 as compared to No-PTCy (0/6, 0/4, 5/16 respectively, p=0.04). The 100-day treatment-related mortality (TRM) was significantly lower in PTCy-25 as compared to PTCy-50 and No-PTCy (0/4, 2/6, 2/16 respectively, p<0.001). There was no viral reactivation (EBV/CMV) in PTCy-25 as compared to 1/6 in PTCy-50 and 5/16 in No-PTCy (p=0.54). The length of hospital stay (LOS) for transplant and the median days for neutrophil recovery (NR) were shorter in PTCy-25 as compared to PTCy-50 and No-PTCy (25.5 days, 31 days and 28.5 days respectively for LOS, p=0.60; 15.5 days, 22 days and 17.5 days for NR, p=0.87). Although the overall survival (OS) seems to favor PTCy-25 (Figure 1), it is limited by short follow up. Conclusion De-escalating the dose of PTCy to 25mg/kg x 2 in GVHD prophylaxis regimens appears to be efficacious and safe in patients receiving matched allogenic transplant. Further prospective studies including a larger patient sample and longer follow-up is warranted to investigate lower PTCy dosing in matched transplants over the current standard dosing. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Post-transplant cyclophosphamide containing regimens after matched sibling, matched unrelated and haploidentical donor transplants in patients with acute lymphoblastic leukemia in first complete remission, a comparative study of the ALWP of the EBMT

Journal of Hematology & Oncology ◽

10.1186/s13045-021-01094-2 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Jaime Sanz ◽

Jacques-Emmanuel Galimard ◽

Myriam Labopin ◽

Boris Afanasyev ◽

Moiseev Ivan Sergeevich ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Cumulative Incidence ◽

Lymphoblastic Leukemia ◽

Hematopoietic Stem ◽

Free Survival ◽

Post Transplant ◽

Gvhd Prophylaxis ◽

Donor Type ◽

Matched Sibling ◽

The Impact

Abstract Background There is no information on the impact of donor type in allogeneic hematopoietic stem cell transplantation (HCT) using homogeneous graft-versus-host (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy) in acute lymphoblastic leukemia (ALL). Methods We retrospectively analyzed outcomes of adult patients with ALL in CR1 that had received HCT with PTCy as GVHD prophylaxis from HLA-matched sibling (MSD) (n = 78), matched unrelated (MUD) (n = 94) and haploidentical family (Haplo) (n = 297) donors registered in the EBMT database between 2010 and 2018. The median follow-up period of the entire cohort was 2.2 years. Results Median age of patients was 38 years (range 18–76). Compared to MSD and MUD, Haplo patients received peripheral blood less frequently. For Haplo, MUD, and MSD, the cumulative incidence of 100-day acute GVHD grade II–IV and III–IV, and 2-year chronic and extensive chronic GVHD were 32%, 41%, and 34% (p = 0.4); 13%, 15%, and 15% (p = 0.8); 35%, 50%, and 42% (p = 0.01); and 11%, 17%, and 21% (p = 0.2), respectively. At 2 years, the cumulative incidence of relapse and non-relapse mortality was 20%, 20%, and 28% (p = 0.8); and 21%, 18%, and 21% (p = 0.8) for Haplo, MUD, and MSD, respectively. The leukemia-free survival, overall survival and GVHD-free, relapse-free survival for Haplo, MUD, and MSD was 59%, 62%, and 51% (p = 0.8); 66%, 69%, and 62% (p = 0.8); and 46%, 44%, and 35% (p = 0.9), respectively. On multivariable analysis, transplant outcomes did not differ significantly between donor types. TBI-based conditioning was associated with better LFS. Conclusions Donor type did not significantly affect transplant outcome in patient with ALL receiving SCT with PTCy.

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Antithymocyte Globulin-Based Prophylaxis for Graft Versus Host Disease Compared to Post-Transplant Cyclophosphamide-Based Prophylaxis in Matched Unrelated Donor Transplantation

Blood ◽

10.1182/blood.v128.22.2307.2307 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2307-2307

Author(s):

Sara Redondo Velao ◽

Mi Kwon ◽

Diana Champ ◽

MJ Pascual Cascon ◽

Pascual Balsalobre ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Cumulative Incidence ◽

Antithymocyte Globulin ◽

Acute Gvhd ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Matched Unrelated Donor ◽

Graft Versus Host ◽

Gvhd Prophylaxis

Abstract INTRODUCTION Post-transplant high-dose cyclophosphamide (PTCy) has shown to prevent graft versus host disease (GvHD) after haploidentical allogeneic hematopoietic cell transplantation (HSCT). Although less extended, its use after matched unrelated donor (MUD) HSCT in combination with additional immunosuppression has been encouraging. The aim of this study was to analyze and compare outcomes of antithymocyte globulin based (ATG) versus PTCy-based GvHD prophylaxis in matched unrelated donor HSCT. MATERIAL AND METHODS We retrospectively analyzed 51 MUD (8/8 HLA-matched) transplants performed in two Spanish centers: 25 received ATG-based prophylaxis and were performed from 2010 to 2013, and 26 received PTCy-based prophylaxis and were performed from 2013 to 2016. RESULTS Characteristics of patients and post-HSCT complications are detailed in Table 1. There were no significant differences in age, gender, diagnosis and Disease risk index. For the ATG group, conditioning regimen consisted of fludarabine combined with busulfan (80%) or melphalan (12%), and TBI plus cyclophosphamide (8%). All patients received ATG 2 mg/kg from day -4 to day -2 followed by methotrexate and cyclosporine (CsA). Conditioning regimen for patients from the PTCy group consisted of fludarabine and busulfan (85%) and thiotepa combined with busulfan and fludarabine (15%). GvHD prophylaxis consisted of PTCy 50 mg/kg on days +3 and +4, combined with: CsA plus MMF in 57%, CsA alone in 31%, or tacrolimus plus MMF or sirolimus in 8%, and tacrolimus alone in 4%. With a median follow-up of 58 months for the ATG group and 12 months for the PTCy group, there were no statistically significant differences in overall survival at 18 months (56% vs 85%, p=0.08), in event free survival (56% vs 68%, p=0.5), and in cumulative incidence of relapse (12% vs 18%, p=0.3). Non-relapse mortality at 12 months was significantly higher in the ATG group (32% vs 10%, p = 0.04). The ATG group presented more cases of hepatic toxicity grades I-IV and hemorrhagic cystitis than PTCy group (Table 1). Cumulative incidence of acute GvHD grades II-IV was higher in the ATG group as well as acute GvHD grades III-IV, with no differences in moderate/severe chronic GvHD incidence (Figure A). CONCLUSION In our experience, albeit differences in follow-up and limited number of patients, we conclude that PTCy combined with additional immunosuppression after MUD allogeneic HSCT offers lower rates of acute GvHD together with less toxicity and non-relapse mortality compared to ATG-based prophylaxis. Further analysis including larger series and follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

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Prognostic Effect of ASXL1 Mutations in Patients with MDS and Secondary AML Following MDS After Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v118.21.1709.1709 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1709-1709 ◽

Cited By ~ 1

Author(s):

Christian Koenecke ◽

Felicitas Thol ◽

Patrick Löffeld ◽

Stefanie Buchholz ◽

Michael Stadler ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Cumulative Incidence ◽

Unrelated Donor ◽

Donor Age ◽

Hematopoietic Stem ◽

Frameshift Mutations ◽

Gvhd Prophylaxis ◽

Related Donor

Abstract Abstract 1709 Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for patients with myelodysplastic syndromes (MDS), but it is associated with high mortality and morbidity. Predictors for treatment outcome after HSCT are limited. Recently, mutations in ASXL1 have been described as an independent adverse prognostic marker for MDS patients not undergoing HSCT. The aim of this study was to investigate the prognostic impact of ASXL1 in a large cohort of patients with high risk MDS or secondary AML following MDS (sAML) undergoing HSCT. Patients and Methods: Patients (n=105) with a diagnosis of MDS (34.3%) or sAML (65.7%) who received an allogeneic HSCT at Hannover Medical School between 1996 and 2010 and for whom genomic DNA was available from a time when the disease was active, were evaluated for the presence of ASXL1 mutations by direct sequencing. Patients gave their informed consent in accordance with the Declaration of Helsinki, and the study was approved by the institutional review board of Hannover Medical School. Overall survival (OS) and cumulative incidence of non-relapse mortality endpoints, measured from HSCT, were death (failure) and alive at last follow-up (censored). A Cox proportional hazards model was constructed for multivariate analysis and the two-sided level of significance was set at P <.05. Results: Median follow up from time of transplantation was 3.67 years. Median patient age at time of HSCT was 58 years (range 22–72) and the median donor age was 39 years (range 0–71). Twenty-seven patients (26.0%) were in complete remission and 78 patients (74%) had active disease before transplantation. In MDS, 9, 21, and 6 patients had intermediate-1, intermediate-2, or high risk IPSS, respectively. Low, intermediate, and high risk cytogenetics according to IPSS were found in 40, 21, and 44 patients, respectively. Related donor HSCT was performed in 24 patients (23%), and unrelated donor HSCT in 81 patients (77%). Six patients received bone marrow (6%), two cord blood (2%), and 97 (92%) received peripheral blood stem cells. Myeloablative preparative regimens were used in 17 patients (16%), and a non-myeloablative regimen was given to 88 patients (84%). Mutations in ASXL1 were detected in 21 (20%) patients with 17 (16.2%) mutations being frameshift mutations. Previously, we showed that only frameshift mutations are prognostically relevant in MDS patients and therefore considered only those for further analysis. ASXL1 frameshift mutations were not correlated with clinical parameters (age, sex, MDS vs. sAML, cytogenetics, bone marrow blasts, blood group, CMV status of patient, type of previous treatment, and remission status prior to transplantation). ASXL1 frameshift mutated patients had received a graft from a related donor (41 vs. 19%, respectively, P=.05) and from bone marrow (17.6 vs. 3.4%, respectively, P=.03) more often compared to wildtype patients, however, there were no differences regarding other transplant-related characteristics (reduced intensity vs. standard conditioning, GvHD prophylaxis, donor age, donor sex, and CMV compatibility between recipient and donor). The presence of ASXL1 frameshift mutations was associated by trend with a shorter overall survival (5-year OS 31 vs. 47%, HR 1.87; 95%CI 0.96–3.64; p=.06). In multivariate analysis, when considering variables with P<.1 in univariate analysis (karyotype, stage [MDS vs. sAML], CMV serostatus of patient, donor type [related vs. unrelated], donor sex, donor age, and GvHD prophylaxis), ASXL1 frameshift mutations were an independent prognostic marker for OS (HR 2.63; 95%CI 1.29–5.38; P=.008) besides karyotype, stage, donor type, and GvHD prophylaxis. The cumulative incidence of relapse was similar between ASXL1 mutated and wildtype patients (P=.47). However, the cumulative incidence of non-relapse mortality was significantly higher in mutated compared to wildtype patients in univariate (61 vs. 34%, P=.01) and multivariate (P=.03) analysis. Grade III-IV acute GvHD was more frequent in ASXL1 mutated patients (37.5 vs. 7.4%, P=.002), while no extensive chronic GvHD was noted in these patients (0 vs. 20%, P=.14). Summary: ASXL1 frameshift mutations independently predicted worse patient outcome after allogeneic HSCT in MDS and sAML patients in our study. The high rate of non-relapse mortality in ASXL1 mutated patients warrants further investigation. *equal contribution Disclosures: No relevant conflicts of interest to declare.

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Age up to 75 Years Does Not Influence the Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v128.22.3501.3501 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3501-3501

Author(s):

Dipenkumar Modi ◽

Abhinav Deol ◽

Seongho Kim ◽

Kendra Mellert ◽

Marie Ventimiglia ◽

...

Keyword(s):

Overall Survival ◽

Relapse Rate ◽

Cumulative Incidence ◽

Relapse Free Survival ◽

Hematopoietic Stem ◽

Free Survival ◽

Allogeneic Hsct ◽

Gvhd Prophylaxis ◽

Reduced Intensity

Abstract Introduction: Patients with AML and MDS who are age 60 or above represent a discrete group of patients with a different disease biology compared to younger patients. These patients are often not offered allogeneic hematopoietic stem cell transplant (HSCT) as a curative intent because of concern of increased nonrelapse mortality (NRM) and poor overall survival (OS). Hence, the information on transplant outcomes among this population is very limited. Recently with the use of better supportive care measures and reduced intensity preparative regimens, patients greater than 60 are often recommended to proceed to transplant. This study evaluates our single center experience of allogeneic transplantation in patients with MDS and AML aged 60 and older. Patients and Methods: We retrospectively evaluated 60 years or older consecutive patients with AML and MDS who underwent allogeneic HSCT between January 2005 and December 2014. The primary objectives of our study were to determine NRM, relapse, relapse free survival (RFS) and OS at 1 year following transplant. The secondary objectives were to estimate cumulative incidence of acute (aGVHD) and chronic GVHD (cGVHD) at 1 year, length of stay and readmission rate in the first 100 days following transplant. Results: Between January 2005 and December 2014, 159 patients underwent allogeneic HSCT with the median age of 64 (range, 60-75) years and median follow-up duration for OS of 3.34 (95% CI, 2.51-3.87) years. Increasing number of patients were transplanted in recent years, i.e., 67% patients between 2010-2014 compared to 33% between 2005-2009. One hundred three patients (65%) had AML and 56 patients (35%) had MDS. Forty-nine patients (31%) received full intensity regimen and 110 patients (69%) received reduced intensity regimen. Fifty-two patients (33%) underwent allogeneic related transplant and 107 patients (67%) had allogeneic unrelated transplant. Thymoglobulin based GVHD prophylaxis was given in 77 patients (48%) whereas non-thymoglobulin based GVHD prophylaxis was given in 82 patients (52%). The median day to neutrophil and platelet engraftment was 11 (range, 7-22) days and 16 (range, 0-675) days, respectively. Graft failure occurred in 3 patients. At 1-year follow-up, the cumulative incidence of grade II-IV aGVHD was 39.7% (95% CI, 32.0-47.2%), grade III-IV aGVHD was 20.8% (95% CI, 14.9-27.5%) and cGVHD was 54.1% (95% CI, 46.0-61.5%). The cumulative incidence of chronic extensive GVHD was 39.8% (95% CI, 32.1-47.4%). Blood stream infection, cytomegalovirus reactivation, Epstein-Barr virus reactivation, C. difficile diarrhea occurred in 44%, 35%, 22% and 26% of patients, respectively. At 1-year follow-up, NRM was 25.3% (95% CI, 18.8-32.3%), RFS was 53.3% (95% CI, 46.1-61.7%), relapse rate was 21.4% (95% CI, 15.4-28.1%) and OS was 56.4% (95% CI, 49.2-54.7%). The median day of hospitalization following transplant was 26 (range, 19-112) days and almost half (52%) of patients were readmitted in the first 100 days following transplant. Leukemia recurrence was the most common cause of death. Multivariable analysis demonstrated high disease risk index to be the independent predictor of poor RFS, OS and higher relapse rate (p<0.03), whereas non-thymoglobulin based GVHD prophylaxis, higher comorbidity index (≥3) and MDS were found to be associated with higher NRM (p<0.03). Most importantly, age did not shown to have any effect on relapse rate, OS, RFS, or NRM. Conclusion: Our results indicate that allogeneic HSCT is well tolerated and had acceptable NRM, and OS among this group. Hence, older age alone should not be considered a contraindication to HSCT. Figure 1 Overall survival (OS) and relapse-free survival (RFS) estimates. The median OS is 1.60 years (95% CI, 0.94 to 5.00 years) and the median RFS is 1.15 years (95% CI, 0.63 to 3.07 years). The median follow-up time of OS and RFS are 3.34 years (95% CI, 2.51 to 3.87 years) and 3.25 years (95% CI, 2.51 to 3.87 years), respectively. Figure 1. Overall survival (OS) and relapse-free survival (RFS) estimates. The median OS is 1.60 years (95% CI, 0.94 to 5.00 years) and the median RFS is 1.15 years (95% CI, 0.63 to 3.07 years). The median follow-up time of OS and RFS are 3.34 years (95% CI, 2.51 to 3.87 years) and 3.25 years (95% CI, 2.51 to 3.87 years), respectively. Figure 2 Cumulative incidences of aGVHD, cGVHD, relapse and non-relapse mortality after transplantation. Figure 2. Cumulative incidences of aGVHD, cGVHD, relapse and non-relapse mortality after transplantation. Disclosures Deol: Jazz Pharmaceuticals: Consultancy.

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The Path to Cure: Using Haploidentical (haplo) Donors and High-Dose Post-Transplant Cyclophosphamide (PTCy) for Treatment-Naïve and Refractory Severe Aplastic Anemia (SAA)

Blood ◽

10.1182/blood-2019-121900 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 147-147 ◽

Cited By ~ 1

Author(s):

Amy E. DeZern ◽

Marianna Zahurak ◽

Kenneth R. Cooke ◽

David Margolis ◽

Richard J. Jones ◽

...

Keyword(s):

Bone Marrow ◽

Cumulative Incidence ◽

Red Blood Cell Transfusion ◽

High Dose ◽

Hematopoietic Stem ◽

Platelet Recovery ◽

Post Transplant ◽

Donor Chimerism ◽

Treatment Naïve

SAA is a life-threatening hematopoietic stem cell disorder that is often treated with bone marrow transplantation (BMT) to reconstitute hematopoiesis and eliminate clonality. Our group has shown that PTCy after related HLA-haplo BMT can facilitate engraftment and yield low rates of relapsed and refractory (R/R) SAA. Given the risk of relapse or secondary clonal disease following immunosuppressive therapy (IST) is > 50% at five years, we decided to implement this treatment paradigm in untreated SAA. Here, we review the haplo outcomes in SAA, with an update in R/R SAA patients and new results in treatment-naïve (TN) SAA patients using haplo donors and PTCy. Patients were eligible with SAA. Fanconi anemia and short telomere patients were excluded. R/R patients had ≥ one course of IST. The conditioning regimen included standard published haplo backbone of antithymocyte globulin, low dose CY, and total body irradiation (TBI). All R/R patients received 200cGy. The TBI dose for the TN cohort was modified after 3 graft failures (GF) in initial 7 patients treated at 200cGy; thus, the last 8 TN patients received 400cGy. After the marrow graft was infused on day 0, cyclophosphamide 50mg/kg/day IV on days +3,+4 post-transplant was administered. All received mycophenolate mofetil beginning day +5 through 35 and tacrolimus day +5 to 365. Engraftment definitions include: absolute neutrophil count >1.0 x10E9/L for three consecutive days; days from last red blood cell transfusion for hemoglobin and platelet count >50,000 for 7 days without transfusion. Thirty-five SAA patients received haplo BMT: 20 R/R and 15 TN. The median follow-up is 31 months (90% CI: 26.0, 45.4). The median age was 25 (range, 4-69) years, with 23 patients > age 20 and 57% were males. The median related haplo donor age was 34 years (range, 19-57), including three non-first degree relatives. Table 1 shows data by cohort. Median time to neutrophil recovery was 17 days (range 15-88), to red cell recovery 23 days (range 6-58) and to platelet recovery 28 days (range 15-108). At the time of BMT, 25 of 35 patients had evidence of clonality (mostly PNH clones). Four of 35 patients (11.4%) (95% CI: 3.2, 26.7%) experienced GF. There was one GF out of 20 patients in the R/R group (5%) (95% CI: 0.1, 24.9%) and 3 of 15 in the TN group 20% (95% CI: 4.3,48.1%, p= 0.20). OS for all patients (Figure 1) is 94% (90% CI: 88,100%) at one and two years, 100% in the R/R group and 86% (90% CI: 72, 100%) in the TN group. The cumulative incidence of grade II-IV aGVHD at day 100 is 9% (90% CI: 1, 17%). The cumulative incidence of chronic GVHD at 2 years is 9% (90% CI: 1,17%). All R/R patients are alive and well, and fully engrafted with 100% donor chimerism; patient with primary GF is 100% chimeric after 2nd transplant from different haplo donor. One patient has extensive cGVHD. Of the first 7 TN patients who received 200cGy TBI, 4 are fully engrafted and well; of the 3 with GF, 2 died from infection and one is now 100% chimeric using second haplo donor. After increasing the TBI dose to 400cGy, the subsequent 8 patients are alive with full donor chimerism. Nonmyeloablative haplo BMT with PTCy represents a potential cure in SAA, with all 20 R/R currently alive, disease-free (including eradication of clonal diseases), and no evidence of active GVHD. Extending this approach to TN patients was associated with higher GF rates. Perhaps this is not surprising given that the potential beneficial effect of front-line IST on engraftment is absent. The increase in TBI dose to 400cGy in TN patients appears to achieve more durable engraftment without early greater toxicity (infection, delayed engraftment, GVHD); more patients and longer follow up are required to understand rates of fertility and other survivorship issues. Alternative donor BMT (including haplo donors) should be offered to all SAA patients with R/R SAA who are fit enough to tolerate non-myeloablative conditioning. A potential advantage of haplo donors over unrelated donors is that the transplant center has full control and oversight of allograft quality, which can be especially important with the use of the preferred allograft source for SAA, bone marrow. Non-myeloablative haplo BMT in TN SAA could lead to a paradigm-shift in the field, such that essentially all children and fit adults can proceed quickly to a relatively safe, curative BMT. Disclosures DeZern: Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Cooke:Jazz pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Impacts of thymoglobulin in patients with acute leukemia in remission undergoing allogeneic HSCT from different donors

Blood Advances ◽

10.1182/bloodadvances.2018025643 ◽

2019 ◽

Vol 3 (2) ◽

pp. 105-115 ◽

Cited By ~ 13

Author(s):

Manabu Wakamatsu ◽

Seitaro Terakura ◽

Kazuteru Ohashi ◽

Takahiro Fukuda ◽

Yukiyasu Ozawa ◽

...

Keyword(s):

Acute Leukemia ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Relapse Free Survival ◽

Hematopoietic Stem ◽

Free Survival ◽

Graft Versus Host ◽

Gvhd Prophylaxis ◽

Related Donor

Abstract Antithymocyte globulin (ATG) is widely used to reduce acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD). To clarify the different impacts of ATG for conditioning across different donor types, we retrospectively analyzed patients with acute leukemia (n = 6617) who underwent hematopoietic stem cell transplantation between 2008 and 2015 with ATG (n = 279) or without ATG (n = 6338). Because thymoglobulin is the only ATG drug approved for GVHD prophylaxis in Japan since September 2008, we included thymoglobulin alone in the present analysis. The survivors’ median follow-up time was 1081 days. Patients were categorized into 5 groups: cord blood (CB; n = 1915), matched related donor (n = 1772), 1-antigen mismatched related donor (1-MMRD; n = 225), matched unrelated donor (MUD; n = 1742), and 1-allele mismatched unrelated donor (1-MMUD; n = 963). In multivariate analysis, ATG decreased overall survival (hazard ratio [HR], 1.403; P = .054) and GVHD-free/relapse-free survival (GRFS) (HR, 1.458; P = .053) in association with increased nonrelapse mortality (NRM) (HR, 1.608; P = .03) with CB, whereas it improved GRFS (HR, 0.515; P < .01) and decreased grades II to IV aGVHD (HR, 0.576; P < .01), extensive cGVHD (HR, 0.460; P = .02), and NRM (HR, 0.545; P = .03) with 1-MMUD. ATG did not impact survival with 1-MMRD and MUD. The use of ATG in conditioning is beneficial due to the reduction in acute/chronic GVHD without increasing NRM or disease relapse only in 1-MMUD transplantation. On the other hand, ATG is not recommended for CB transplantation.

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Low-dose antithymocyte globulin plus low-dose posttransplant cyclophosphamide combined with cyclosporine and mycophenolate mofetil for prevention of graft-versus-host disease after HLA-matched unrelated donor peripheral blood stem cell transplantation

Bone Marrow Transplantation ◽

10.1038/s41409-021-01358-y ◽

2021 ◽

Author(s):

Xi Sun ◽

Jun Yang ◽

Yu Cai ◽

Liping Wan ◽

Chongmei Huang ◽

...

Keyword(s):

Antithymocyte Globulin ◽

Low Dose ◽

Peripheral Blood Stem Cell ◽

Unrelated Donor ◽

Relapse Free Survival ◽

Matched Unrelated Donor ◽

Free Survival ◽

Graft Versus Host ◽

Gvhd Prophylaxis ◽

Blood Stem Cell Transplantation

AbstractThe standard regimens for graft-versus-host disease (GvHD) prophylaxis in matched unrelated donor (MUD) transplantation were based on antithymocyte globulin (ATG) in combination with calcineurin inhibitors (CNIs). To improve the efficiency of GvHD prophylaxis in MUD peripheral blood stem cell transplantation (MUD-PBSCT), 51 patients with hematological malignancies received a novel regimen for GvHD prophylaxis, which is composed of low dose of ATG (5 mg/kg) plus low-dose posttransplant cyclophosphamide (PTCy, 50 mg/kg) (low-dose ATG/PTCy) combined with cyclosporine A (CsA) and mycophenolate mofetil (MMF). The cumulative incidences (CIs) of grades I–IV and II–IV acute GvHD (aGvHD) were 14.5% (95% CI, 9.4–19.6%) and 6.2% (95% CI, 2.8–9.6%) within 100 days after transplantation, respectively. The CI of mild-to-moderate chronic GvHD (cGvHD) within 1 year was 11.5% (95% CI, 6.6–16.4%). The 1-year probabilities of GvHD and relapse-free survival, relapse-free survival, and over survival were 70.6% (95% CI, 64.2–77.0%), 76.5% (95% CI, 70.6–82.4%), and 82.0% (95% CI, 76.5–87.5%), respectively. The CIs of CMV and EBV reactivation by day 180 were 10.4% (95% CI, 1.5–19.4%) and 8.3% (95% CI, 0.2–16.4%), respectively. The results suggested that low-dose ATG/PTCy combined with CsA/MMF as GvHD prophylaxis in MUD-PBSCT had promising activity.

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